Widespread perturbation of ETS factor binding sites in cancer.
Widespread perturbation of ETS factor binding sites in cancer.
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DOI：
10.1038/s41467-023-36535-8
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发表时间：
2023-02-17
影响因子：
16.6
通讯作者：
Fuxman Bass, Juan Ignacio
中科院分区：
文献类型：
--
作者：
Carrasco Pro, Sebastian;Hook, Heather;Bray, David;Berenzy, Daniel;Moyer, Devlin;Yin, Meimei;Labadorf, Adam Thomas;Tewhey, Ryan;Siggers, Trevor;Fuxman Bass, Juan Ignacio
尽管>90%的体细胞突变位于非编码区，但很少有报道称其为癌症驱动因素。为了预测驱动非编码变体（NCV），我们提出了一种基于启动子中连贯TF功能模型的转录因子（TF）感知负荷测试。我们将该测试应用于来自全基因组泛癌症分析队列的NCV，并预测了20种癌症类型中813个基因的启动子中的2555个驱动NCV。这些基因在癌症相关基因本体、必需基因和与癌症预后相关的基因中富集。我们发现765个候选驱动NCV改变转录活性，510个导致TF-辅因子调节复合物的差异结合，并且它们主要影响ETS因子的结合。最后，我们表明，不同的NCV启动子内往往会影响转录活性，通过共享的机制。我们的综合计算和实验方法表明，癌症NCV是普遍存在的，ETS因素通常被破坏。到目前为止，在非编码区中几乎没有发现癌症驱动因素。在这里，作者开发了一种转录因子感知负荷测试来预测非编码变体，并分析对转录因子结合的影响-特别是ETS因子-以及它们对转录活性的影响。
Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a transcription factor (TF)-aware burden test based on a model of coherent TF function in promoters. We apply this test to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predict 2555 driver NCVs in the promoters of 813 genes across 20 cancer types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We find that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted. Few cancer drivers in non-coding regions have been identified so far. Here, the authors develop a transcription factor-aware burden test to predict non-coding variants and analyze the impact on transcription factor binding - especially ETS factors - as well as their impact on transcriptional activity.
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影响因子：
14.8
作者：
Berger, Michael F.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.
影响因子：
46.9
作者：
Berger, Michael F.;Philippakis, Anthony A.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
20.3
作者：
De Keersmaecker K;Sulima SO;Dinman JD
通讯作者：
Dinman JD
癌症体细胞非编码突变模式的全基因组分析。
影响因子：
56.9
作者：
Dietlein, Felix;Wang, Alex B.;Fagre, Christian;Tang, Anran;Besselink, Nicolle J. M.;Cuppen, Edwin;Li, Chunliang;Sunyaev, Shamil R.;Neal, James T.;Van Allen, Eliezer M.
通讯作者：
Van Allen, Eliezer M.